The Cardiorenal Benefits, Risks of Treating Type 2 Diabetes With SGLT2 Inhibitors

There are compelling reasons to use sodium-glucose cotransporter-2 (SGLT2) inhibitors for the treatment of type 2 diabetes, according to a session at the American Society of Health-System Pharmacists' (ASHP) virtual 2020 ASHP Midyear Clinical Meeting and Exhibition. These reasons include the potential of SGLT2 inhibitors to minimize weight gain and hypoclycemia and reduce atherosclerotic cardiovascular disease risk.

The current FDA-approved SGLT2 inhibitors available in the United States include canagliflozin (Invokana), empagliflozin (Jardiance), dapagliflozin (Farxiga), and ertugliflpzin (Steglatro). Their primary mechanism of action in diabetes decreases the reabsorption of glucose in renal proximal tubules and lowers the renal threshold for glucose.

Based on data, there are also cardiorenal benefits of SGLT2 inhibitors outside of just lowering glucose. These benefits include diueresis/natriuresis/glycosuria, decreased arterial pressure and stiffness, decreased levels of leptin and uric acid, improved myocardial function, reduced intraglomerular pressure/hyperfiltration, and improved tubuloglomerular feedback.

“Lots of different mechanisms [are] at play for where those potential benefits are from a cardiorenal perspective,” said Amanda Stahnke, PharmD, BCACP, during the session.

However, there also existing concerns regarding the adverse events (AEs) that can occur from the use of SGLT2 inhibitors. The most common AEs are in the genitals and urinary tract, Stahnke explained. These include genital fungal infections, urinary tract infections, euglycemic diabetic ketoacidosis, lower limb ulcerations, and soft tissue infections.

With these AEs, there are also potential precautions that should be taken when treating patients with SGLT2 inhibitors. For example, a patient taking an SGLT2 inhibitor who has a planned surgery should discontinue their therapy approximately 3 days before the procedure in order to prevent postoperative ketoacidosis, Stahnke noted.

When used for treatment by themselves, SGLT2 inhibitors are at low risk of hypoglycemia, but when paired with insulin or sulfonylurea, the risk becomes much higher. Additionally, SGLT2 inhibitors can contribute to intravascular volume contraction. For this reason, some providers will stop or reduce the dose of a diuretic as applicable in order to decrease the potential for intravascular volume contraction when adding an SGLT2 to treatment.

Also, since there is the potential risk of lower limb ulcerations and soft tissue infections, if patients have a history of amputation, severe neuropathy, or peripheral vascular disease, providers should approach treatment patients with SGLT2 inhibitors with caution.

Specifically, for canagliflozin, there also exists the potential risk of bone fractures, which should be taken into consideration when considering this SGLT2 inhibitor as a treatment for certain patients.

Additionally, across the board for all SGLT2 inhibitors, there is a contraindication for patients on dialysis. For these patients, SGLT2 inhibitors should not be used, Stahnke noted.

For the necessary renal dosing adjustments for patients with SGLT2 inhibitors, each agent varies. With canagliflozin, for example, it can be continued at 100 mg, even if epidermal growth factor (eGFR) falls below 30, and the urine albumin-to-creatinine ratio is elevated above 300, as long as the patient is not on dialysis, Stahnke explained.

“The other thing with the dosing adjustment I’d like to point out is that sometimes it’s based on the indication that it’s being used for,” Stahnke said.

She explained that for patients with type 2 diabetes, dapagliflozin is contraindicated if eGFR is less than 30. For patients with heart failure, there are insufficient data regarding how to proceed if the eGFR is less than 30.

“Different indications may actually result in different dosing adjustments. So being aware of those particular nuances [is important],” Stahnke said.

For canagliflozin and ertugliflozin, there are warnings regarding the potential for amputation. However, the FDA black box warning was removed from canagliflozin in August of 2020, Stahnke explained.

“So, still a concern, but the more and more data we get, we know it’s maybe something we just need to be cautious [about], but [it’s] not necessarily something that the black box still needs to be present for,” Stahnke said.

Across the board for these agents, the A1C change is similar, with a 0.5 to 1.5 reduction. Similarly, the body weight change is about a 3 kg weight loss for these agents, or potentially a bit more, depending on the agent being used and the patient population it’s being used for.

REFERENCE

Stahnke A, Rosselli J. In Sickness and In Health: Cardiorenal Benefits and Risks of Newer Diabetes Medications. Poster presented at American Society of Health-System Pharmacists' virtual 2020 ASHP Midyear Clinical Meeting and Exhibition; December 6-10, 2020. Accessed December 10, 2020.